Pharmaceutical compositions for lipophilic drugs

ABSTRACT

Stable solutions of lipophilic drugs, such as cyclosporin, forming a polar lipid self-emulsifying drug delivery system. The solutions can include lipophilic drugs, such as cyclosporin, dissolved in a polar lipid, such as having a C 6 -C 12  fatty acid monoglyceride content of at least about 50%, surfactants and triglycerides. The composition forms a fine emulsion on exposure to water. The encapsulated dosage form of this composition needs neither a hydrophilic component nor air-tight blister packaging, and is particularly suitable for oral administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/400,585, filed Apr. 7, 2006, which is a continuation of U.S. patentapplication Ser. No. 09/797,912, filed Mar. 5, 2001, now U.S. Pat. No.7,070,802; which is a continuation of U.S. patent application Ser. No.09/196,353, filed Nov. 19, 1998, now abandoned; which is acontinuation-in-part of U.S. patent application Ser. No. 08/786,314,filed Jan. 22, 1997, now U.S. Pat. No. 5,858,401, which claims thebenefit of U.S. Provisional Patent Application Ser. No. 60/010,410,filed Jan. 22, 1996, the disclosures of which are incorporated byreference herein in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical compositions in the formof self-emulsifying systems. More particularly, the present invention isdirected to pharmaceutical compositions, preferably cyclosporincompositions, which form an emulsion in the presence of aqueous mediaand environments, for example, water and gastrointestinal fluids.

2. Discussion of Background Information

Cyclosporins form a class of polypeptides well known for possessingimmunosuppressive and anti-inflammatory activity. The most commonlyknown cyclosporin is cyclosporin-A, which is commercially available asSandimmune® and Neoral® in soft gelatin capsule dosage form and as aliquid drink-solution.

Cyclosporins are hydrophobic substances exhibiting poor water solubilityand unsatisfactory bioavailability. Oral liquid formulations containingoil, ethanol, and a surfactant such as LABRAFIL®, which is atransesterification product of a triglyceride and a polyol, aredisclosed in U.S. Pat. No. 4,388,307. However, these formulations arecharacterized by a variety of disadvantageous properties, includingunpleasant taste, which make these formulations undesirable forlong-term therapy. Encapsulation in soft gelatin capsules improves thetaste-acceptability of the liquid, but because of the presence of thehydrophilic component (ethanol) in the capsules, they must be packagedin specialized, expensive airtight blister or aluminum foil blisterpacks. The bioavailability of these liquid and soft gel formulations islow (approximately 30%) and also variable.

U.S. Pat. No. 5,342,625 discloses cyclosporin formulations indicated tohave enhanced bioavailability. In addition to cyclosporin, theformulation disclosed in this patent includes a hydrophilic phase, alipophilic phase, and a surfactant. The hydrophilic phase compriseseither 1,2-propylene glycol or an ether of the formulaR₁—(—O—(CH₂)₂)_(x)—OR₂, wherein R₁ is alkyl or tetrahydrofurfuryl, R₂ isalkyl, tetrahydrofurfuryl, or hydrogen, and X is an integer of 1 to 6.Such ethers are commercially available under the trademarks TRANSCUTOL®,COLYCOFUROL®, and GLYCOFUROL®. The hydrophilic phase may additionallycontain C₁-C₅ alkanols, such as ethanol. The formulation disclosed inU.S. Pat. No. 5,342,625, therefore, like those of U.S. Pat. No.4,388,307, requires special packaging, such as aluminum foil blisterpacks. Further, ethers in the formulations disclosed in U.S. Pat. No.5,342,625, such as the indicated TRANSCUTOL® and GLYCOFUROL , arerestricted by several regulatory agencies worldwide, including theUnited States Food and Drug Administration, because these compounds arenot considered “generally recognized as safe” (G.R.A.S.) for oral use.

U.S. Pat. No. 5,154,930 discloses lipophilic drug compositions whichform suspensions of lipid aggregates when introduced to an aqueous phaseand agitated. Illustrations of the invention include compositions ofcyclosporin A. The compositions comprise a non-aqueous water-misciblesolvent (hydrophilic phase), preferably ethanol or polyethylene glycol.The compositions also require a desalted charged lipid which is solublein the water-soluble solvent, and which exhibits limited sedimentationupon dispersal in the aqueous medium of suspension formation.

There is a need for improved formulations that can be inexpensively andconventionally packaged, such as in glass or O.H.D. polyethylenebottles. There is also a need for formulations, e.g., oral formulations,whose components comprise only G.R.A.S. excipients.

Alcohol-free pre-emulsion concentrates are known, but also have flaws.For example, the formulation of U.S. Pat. No. 5,206,219 requires amultitude of ingredients, including a protease inhibitor, cholesterol, aphospholipid, a surfactant, a polyol, and a lipid solvent.

U.S. Pat. No. 4,990,337 discloses solutions of cyclosporin inmonoglycerides or diglycerides of C₆ to C₁₀ fatty acids, preferably in aC₈ diglyceride, which can be emulsified in water. All of the examplesdescribe preparing emulsions by making two solutions—one containingcyclosporin and a fatty acid glyceride, and the other containing waterwith a small amount of surfactant—mixing the solutions, and emulsifyingthem with laboratory equipment. Although Test Example 2 discloses thatcapric acid monoglyceride, when shaken with water, would emulsify in amanner “very close to self-emulsification,” there is no teaching orsuggestion of how to prepare a cyclosporin composition which forms afine emulsion on contact with an aqueous phase.

U.S. Pat. No. 5,759,997, discloses compositions comprising cyclosporin,a mixture of mono-, di-, and triglycerides, and a hydrophilic tenside.In one embodiment, the mixture of mono-, di-, and triglycerides comesfrom a single product, such as MAISINE®, whose; fatty acid component ismainly long chain. There is no suggestion that these compositions wouldself-emulsify, nor is there any discussion of how to prepare acyclosporin composition which forms a fine emulsion on contact with anaqueous phase.

SUMMARY OF THE INVENTION

Lipophilic drug compositions, e.g., cyclosporin compositions, have beendiscovered which unexpectedly, completely and reliably self-emulsifyupon contact with an aqueous phase, such as water or gastrointestinalfluid. In particular, it has been found that lipophilic drugs, such ascyclosporin, exhibit superior self-emulsification ability when dissolvedin certain polar lipids, and mixed with a sufficient amount of at leastone surfactant.

The present invention is generally described as a “Polar LipidSelf-Emulsifying Drug Delivery System,” or PLSEDDS. In the presentinvention, a novel pharmaceutical formulation for lipophilic drugs, suchas cyclosporin, is provided in the form of a PLSEDDS which overcomesproblems associated with prior art formulations. The ready-to-usePLSEDDS of the instant invention comprises a lipophilic drug, such ascyclosporin, which is dissolved in a polar lipid and mixed withsufficient surfactant, such that upon contact with an aqueous medium,the composition completely forms a fine emulsion of mean particle sizeof less than about 50 nm, preferably less than about 30 nm, with apreferred range being from about 15 nm to 30 nm.

PLSEDDS compositions confer several desirable attributes to cyclosporinformulations. For example, the PLSEDDS formulations described herein (i)instantly or spontaneously form fine emulsions on exposure to water orgastrointestinal fluid without the need for specialized equipment, (ii)do not require a hydrophilic cosolvent, and (iii) do not need air tightaluminum blister packaging or other specialized expensive packaging, and(iv) are shelf-stable.

In one aspect, the present invention is directed to a shelf-stablepharmaceutical solution comprising at least one lipophilic drug; asurfactant component; and a polar lipid component, which solution, oncontact with an aqueous phase, is capable of spontaneously forming afine emulsion.

Still further the present invention is directed to a shelf-stablepharmaceutical solution comprising at least one cyclosporin; asurfactant component; and a polar lipid component, wherein the at leastone cyclosporin, the surfactant component, and the polar lipid componentare present in effective amounts so that the composition, on contactwith an aqueous phase, is capable of spontaneously forming a fineemulsion.

Further aspects of the invention, including discussion of specific andpreferred components of the solution, such as the lipophilic drug, thesurfactant component, the polar lipid component and the inclusion ofadditional components, such as triglyceride, as well as various formsfor administration, are discussed further herein.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all percentages, parts, ratios, etc. statedherein are by weight. Moreover, all percent values in this application,unless otherwise stated, are calculated by weight based upon 100% of agiven sample weight. Thus, for example, 30% represents 30 weight partsout of every 100 weight parts of the sample.

Unless otherwise stated, a reference to a compound or component,includes the compound or component by itself, as well as in combinationwith other compounds or components, such as mixtures of compounds.

The PLSEDDS compositions of the present invention form fine emulsions oncontact with an aqueous phase, such as water or gastrointestinal fluids.The compositions comprise (i) at least one lipophilic drug, (ii) a polarlipid component, and (iii) a surfactant component. The compositions mayfurther include (iv) a triglyceride component.

In particular, it has been found that when cyclosporin is dissolved incertain polar lipids, the presence of a sufficient amount of at leastone surfactant in the cyclosporin solution obviates the need for ahydrophilic component, such as disclosed in U.S. Pat. No. 5,342,625. Inthe composition of the invention, there is therefore no need for adistinct hydrophilic phase. In other words, the composition of thepresent invention is a solution and therefore does not contain distincthydrophilic and lipophilic phases.

On exposure to an aqueous medium, such as water or gastrointestinalfluid, the composition of the present invention instantly orspontaneously forms a fine emulsion. A fine emulsion preferably has amean particle size, e.g., diameter, of less than about 50 nm, even morepreferably less than about 30 nm, with a preferred range being fromabout 15 nm to 30 nm, when measured by photon correlation spectroscopy(PCS) with the particle size being determined using equipment such as aMalvern Zetasizer 1000 (Malvern Instruments Limited, Malvern, UK).Moreover, because no emulsification equipment is required, the formationof the emulsion on contact with an aqueous phase is referred to asself-emulsification. While no agitation and/or emulsification equipmentis required to obtain emulsification, agitation and/or emulsificationequipment can be utilized.

As discussed herein, lipophilic drugs comprise those drugs which aresoluble in polar lipids. These drugs include, but are not limited to,cyclosporins, e.g., cyclosporin A; growth hormones; protease inhibitors;angiotensin-converting enzyme (ACE) inhibitors; cis- and trans-retinoidsand their derivatives; parathyroid hormones and hormone analogs; andinsulins. Also included are other water-insoluble peptides and proteinssuch as waterinsoluble peptides having a molecular weight of about 400to about 3,000; and waterinsoluble proteins having molecular weightsabove about 3,000.

Preferably, the lipophilic drugs are polypeptide lipophilic drugs,especially monocyclic polypeptides, in particular the cyclicundecapeptides which form the class of drugs known as the cyclosporins.As discussed herein, the terms cyclosporin and cyclosporins refer to anyof the several cyclosporins, and to any two or more of the severalcyclosporins, such as in a mixture. In addition to the preferredcyclosporin, cyclosporin-A, other naturally occurring cyclosporinanalogs include cyclosporins -B, -C, -D, -E, -F, -G, and so on. Alsoincluded are non-naturally occurring cyclosporins, includingdihydrocyclosporins, such as dihydrocyclosporin-C and -D;isocyclosporins, such as isocyclosporin-D; other cyclosporinderivatives; and synthetically prepared cyclosporin analogs. Thecyclosporin most commonly used is cyclosporin-A, and is commerciallyavailable as a mixture which also contains smaller amounts of othercyclosporin analogs.

The lipophilic drug, e.g., cyclosporin, such as cyclosporin-A, maycomprise about 5 to 20 wt. %, more preferably about 7 to 14 wt. %, andstill more preferably about 7 to 10 wt. % of the composition Twoparticularly preferred embodiments comprise about 8 wt. % or about 10wt. % cyclosporin.

The polar lipid component, as discussed herein, comprises one or morepartial glycerides, preferably including one or more fatty acid partialglycerides. Fatty acid partial glycerides, as discussed herein, aremonoglycerides and diglycerides. Suitable monoglycerides includeα-monoglycerides and β-monoglycerides. Suitable diglycerides includeα,α′-diglycerides and α,β-diglycerides, wherein the fatty acid residuesmay be the same or different.

Preferable polar lipid components, therefore, include polar lipidcomponents which comprise one or more partial glycerides, morepreferably one or more fatty acid partial glycerides, e.g., one or moremonoglycerides and/or one or more diglycerides—particularly, one or moremonoglycerides and/or one or more diglycerides of at least one fattyacid. Monoglycerides and diglycerides of C₆-C₁₂ fatty acids arepreferred, more preferably C₈-C₁₀ fatty acids. Preferable polar lipidcomponents comprise at least about 45wt. %, such as at least about 50wt. %, at least about 55 wt. %, and about 60 wt. % monoglyceride of atleast one C₆-C₁₂ fatty acid, more preferably at least one C₈-C₁₀ fattyacid. In one preferred embodiment, the polar lipid component comprisesC₆-C₁₂ fatty acid mono- and di- glycerides comprising from about 55 wt %to 65 wt. % of the polar lipid component.

Preferably, the fatty acid component comprises at least about 80 wt. %,more preferably at least about 90 wt. %, even more preferably at leastabout 95 wt. %, and even more preferably at least about 99 wt. % of C₈fatty acids, such as caprylic acid, by weight of the fatty acid in thepolar lipid component. Of these compositions, particularly preferred arethose where the remainder of the fatty acid component consists of, orconsists essentially of, or comprises, a C₁₀ fatty acid, such as capricacid, whereby the fatty acid chains preferably consist of, or consistessentially of, or comprise, C₈ fatty acid, such caprylic acid, and, C₁₀fatty acid, such as capric acid.

Suitable products useful as polar lipid components are marketed byAbitec Corporation of Janesville, Wis. under the trademarks CAPMUL® MCMand CAPMUL® MCM C₈. Particularly, CAPMUL® MCM as disclosed in the AbitecGroup Product Information Sheet entitled “CAPMUL® MCM,” Issue:3, Date:March 1994, and in the Abitec Corporation Mar. 17, 1997 “Certificate ofAnalysis” for CAPMUL® MCM; Lot No: 60502-6, and CAPMUL® MCM C₈ asdisclosed in the Abitec Group Product Information Sheet entitled “CAPMULMCM C₈ CAS # 26402-22-2,” Issue:2, Date: Oct. 31, 1996, and in theAbitec Corporation Feb. 6, 1997 “Certificate of Analysis” for CAPMUL®MCM (C8); Lot No.: 60114-8, may be used. These Product InformationSheets and Certificates of Analysis are hereby incorporated herein intheir entireties by reference thereto.

The polar lipid component may comprise from about 5 wt. % to 50 wt. %,more preferably from about 20 wt. % to 50 wt. %, and even morepreferably about 30 wt. % to 45 wt. % of the composition of theinvention.

The surfactant component of the invention may include one or moresurfactants. While various surfactants can be utilized, nonionicsurfactants, particularly hydrophilic nonionic surfactants, arepreferred. The surfactant component preferably has an 1-11LB(hydrophilic-lipophilic balance) of from about 10 to 16, and morepreferably from about 12 to 14. Where the surfactant component includestwo or more surfactants, each or any surfactant in the surfactantcomponent preferably has an HLB of about from 10 to 16, and morepreferably from about 12 to 14.

Among the surfactants which may be used are the reaction products ofnatural or hydrogenated vegetable oils and ethylene oxide, as disclosedin U.S. Pat. No. 5,342,625, which is hereby incorporated herein in itsentirety by reference thereto. These include polyoxyethylated naturalvegetable oils, such as polyoxyethylated natural castor oils, andpolyoxyethylated hydrogenated vegetable oils, such as polyoxyethylatedhydrogenated castor oils. In accordance with the foregoing,polyoxyethylene glycerol triricinoleate, PEG(35) natural castor oil,PEG(35) hydrogenated castor oil, PEG(40) natural castor oil, and PEG(40)hydrogenated castor oil may be used.

Appropriate commercially available surfactants include CREMOPHOR® RH40,a PEG(40) hydrogenated castor oil, and CREMOPHOR® EL, a PEG(35) naturalcastor oil, these being sold by BASF Corporation of Midland, Mich.Particularly, CREMOPHOR® EL, as disclosed in the BASF April 1996Technical Bulletin entitled “CREMOPHOR EL; CTFA/INCI: PEG-35 CastorOil,” is preferred for the surfactant component. This Technical Bulletinis hereby incorporated herein in its entirety by reference thereto.

Another useful class of surfactants comprise polyglycolyzed glyceridesor ethoxylated glycerides having a molecular weight of PEG from about400 to about 2,000 and a fatty acid chain length of from six to eighteencarbon atoms; particularly, polyglycolyzed C₈-C₁₀ glycerides, and mostespecially saturated polyglycolyzed C₈-C₁₀ glycerides, are suitable.Examples of substances that may be used include PEG(8) caprylic-capricglyceride, e.g., LABRASOL®), sold by Gattefosse Corporation of Lyon,France. LABRASOL is characterized in the Gattefosse IV/92/2 two pageData Sheet entitled “LABRASOL,” which is hereby incorporated herein inits entirety by reference thereto.

Other surfactants that may be used include polyoxyethylene sorbitanesters, i.e., lauryl, palmityl, stearyl, oleyl and trioleyl esters ofpolyoxyethylene sorbitan, which are commercially available as TWEEN® 20(polysorbate 20), TWEEN® 40 (polysorbate 40), TWEEN® 60 (polysorbate60), TWEEN® 80 (polysorbate 80) and TWEEN® 85 (polysorbate 85),respectively.

A particularly suitable combination of surfactants comprises apolyoxyethylated natural or hydrogenated castor oil, such as PEG(35)natural castor oil, PEG(40) hydrogenated castor oil, and CREMOPHOR® EL,with CREMOPHOR® EL being preferred, as a first surfactant, and apolyglycolyzed C₈-C₁₀ glyceride, preferably LABRASOL®, as a secondsurfactant. The composition preferably comprises from about 50 to 60 wt.% of the first and second surfactants. A weight ratio of firstsurfactant to second surfactant of from about 1:1 to 20:1, preferablyabout 1:1 to 9:1, more preferably 3:1 to 9:1, and most preferably from ,about 5:1 to 9:1, is especially preferred.

The surfactant component may comprise from about 30 to 75 wt. %,preferably about 45 to 60 wt. % by weight of the composition. Particularembodiments include about 50 wt. %, 56 wt. %, 67 wt. %, 63 wt. % or 73wt. % surfactant by weight.

Although the above specifically recited surfactants, mixtures, andconcentrations are preferable, any surfactant or mixture of surfactants,at any concentration, can be utilized that enables self-emulsificationof the composition when the composition is added to an aqueous medium.

The composition of the invention can further include a triglyceridecomponent. The triglyceride component can comprise one or moretriglyceride compositions—particularly, one or more triglycerides of atleast one fatty acid, preferably C₆-C₁₂ fatty acid, more preferablyC₆-C₁₀ fatty acid. The fatty acid triglycerides as disclosed in U.S.Pat. No. 5,342,625, which is incorporated by reference in its entirety,may be employed.

A commercially available triglyceride composition that may be used isLABRAFAC LIPOPHILE WL 1349, available from Gattefosse Corporation, Lyon,France. Particularly, this composition as disclosed in the IV/92/II twopage Data Sheet entitled “LABRAFAC LIPOPHILE WL 1349” is appropriate forthe triglyceride component. This Data Sheet is hereby incorporatedherein in its entirety by reference thereto.

When present, the triglyceride component preferably comprises about 10wt. % or less of the composition, more preferably less than about 5 wt.%, with a preferred range being about 1 to 5 wt. %, more preferablyabout 2 to 4 wt. %, of the composition of the invention. Particularembodiments comprise about 2.5 wt. % or about 10 wt. % triglyceridecomponent.

The composition of the invention may further contain additives, forexample, sweetening agents, and/or stabilizers such as one or moreantioxidants and/or preservatives. Vitamin E (dl-α-tocopherol) is apreferred antioxidant. A commercial Vitamin E composition that may beused is available from Hoffmann-La Roche Inc. of Belvedere, N.J. Thecomposition as disclosed in the Jul. 7, 1997 Hoffmann-La Roche Inc.Quality Control Department sheet, entitled “605250003DL-AL-TOCOPH-USP/FCC”, is suitable. This sheet is hereby incorporatedherein in its entirety by reference thereto.

An advantage of the compositions of the present invention is shelfstability, which preferably includes both chemical and physicalstability. Chemical stability includes stability of the compositionagainst chemical degradation, e.g., hydrolysis, oxidation/reduction,photolysis, etc. Physical stability refers to stability against changein physical form, including, e.g., no, or essentially no,crystallization of the active ingredient from the solution. Compositionsare preferably shelf-stable for at least the interval from when thecomposition is manufactured to the time when the patient couldreasonably be expected to take the composition. Compositions are alsopreferably shelf-stable when subjected to typical manufacturing andmarketing conditions, such as storage and transportation. Compositionsof the present invention are preferably shelf-stable for at least threemonths under accelerated challenge conditions (40° C. and 75% relativehumidity) and for at least two years under recommended storageconditions, such as ambient temperature.

Compositions examined without a polar lipid component, such as a C₆-C₁₂monoglyceride, are not shelf-stable, as evidenced by crystallization onstorage at room temperature for as little as one day. Thisshelf-instability renders them unsuitable for practical use. Cyclosporinformulations of the present invention, containing a polar lipidcomponent, were shelf-stable for at least three months, and did notundergo crystallization of cyclosporin under accelerated challengestorage conditions.

PLSEDDS compositions of the present invention, therefore, includecompositions comprising a lipophilic drug, a polar lipid component, anda surfactant component and optionally a triglyceride component havingthe ability to form fine emulsion upon contact with an aqueousenvironment, and preferably in the proportions, described above. In thisregard, as will be recognized by those of ordinary skill in the art, thepresent invention is not limited to the disclosed proportions ofingredients. Any composition, preferably shelf-stable, havingproportions of lipophilic drug, polar lipid, surfactant, and(optionally) triglyceride, which is capable of instantly orspontaneously forming an emulsion on contact with an aqueous phase iswithin the scope of the present invention.

Thus, one particular composition of the present invention can comprisefrom about 7 to 14 wt. % cyclosporin, from about 30 to 50 wt. % polarlipid component (preferably partial glycerides of C₆-C₁₂ fatty acids),from about 40 to 60 wt. % surfactant component, and optionally, fromabout 2% to 4 wt. % triglyceride component.

Another preferred composition comprises from about 7 to 10 wt. %cyclosporin; from about 30 to 45 wt. % polar lipid component, whereinthe polar lipid component comprises at least 45 wt. % monoglyceride ofC₆-C₁₂ fatty acids; from about 45 to 60 wt. % surfactant component; andoptionally, from about 2 wt. % to about 4 wt. % triglyceride component.

Still another especially preferred composition comprises from about 7 to10 wt. % cyclosporin A; from about 30 to 45 wt. % polar lipid.component, wherein the polar lipid component comprises about 60 wt. %monoglyceride of caprylic and capric acids; about 50 to 60 wt. %surfactant component, wherein the surfactant component comprises a firstsurfactant comprising a polyoxyethylated castor oil, preferably aPEG(35) natural castor oil, and a second surfactant comprising asaturated polyglycolyzed C8-C10 glyceride, preferably in a weight ratioof first surfactant to second surfactant of from about 5:1 to about 9:1;and from about 2 to 4 wt.% triglyceride component.

Still another especially preferred composition comprises from about 7 to10 wt. % cyclosporin A; from about 30 to 45 wt. % polar lipid componentcomprising about 60 wt. % monoglycerides of caprylic and capric acids;and from about 45 to 60 wt. % surfactant component, wherein thesurfactant component comprises a polyoxyethylated castor oil, preferablya PEG(35) natural castor oil.

Still another preferred composition comprises from about 7 to 10 wt. %cyclosporin A; from about 20 to 30 wt. % polar lipid componentcomprising about 60 wt. % monoglycerides of caprylic and capric acids;and about 60 to 70 wt. % surfactant component, wherein the surfactantcomponent comprises a polyoxyethylated castor oil, preferably a PEG(40)hydrogenated castor oil.

Still another preferred composition comprises from about 7 to 10 wt. %cyclosporin A; from about 5 to 10 wt. % polar lipid component comprisingabout 60% monoglycerides of caprylic and capric acids; from about 65 to80 wt. % surfactant component, wherein the surfactant componentcomprises a mixture of polyoxyethylated castor oil, preferably a PEG(40)hydrogenated castor oil, and polyglycolyzed or ethoxylated glycerides,in a weight ratio of from about 1:1 to 3:1; and less than about 10 wt. %of a triglyceride component.

The following examples provide additional information on some of thecompositions of the present invention. It should be understood thatthese examples are not meant to constitute a comprehensive list of thescope of the invention. Other compositions within the scope of theinvention can be prepared, as will be understood by those of ordinaryskill in the art.

EXAMPLE 1

Cyclosporin-A (1.0 g) was dissolved in Capmul® MCM (5.0 g) at 25° C. to30° C. Tween 80 (6.0 g) was added and then mixed to achieve ahomogeneous sohition. The mixture appeared as a clear solution to thenaked eye, and a microscopic analysis revealed no crystals. An amount ofthe solution, such that each capsule contained 50 mg of cyclosporin, wasfilled into soft gelatin capsules.

EXAMPLE 2

Cyclosporin (1.0 g) was dissolved in Capmul® (MCM) (2.3 g) at 25° C. to30° C. LABRASOL® (4.5 g) and PEG-400 (0.76 g) were added and mixed toachieve a homogenous solution. The mixture appeared as a clear solutionto the naked eye, and a microscopic analysis revealed no crystals. Anamount of the solution, such that each capsule contained 100 mg ofcyclosporin, was filled into soft gelatin capsules.

EXAMPLES 3-5

The remaining examples were made according to the above procedure. Thequantities are listed in the following table in grams:

Ingredients Example 3 Example 4 Example 5 Cyclosporin 0.50 0.50 0.50CAPMUL ® MCM 2.50 2.00 2.00 LABRASOL ® — 1.26 1.26 TWEEN 80 2.50 1.28 —TWEEN 20 — — 1.28 Total 5.50 5.04 5.04

In each case, the mixture appeared as a clear solution to the naked eye,and a microscopic analysis revealed no crystals. An amount of thesolution, such that each capsule contained 50 mg of cyclosporin, wasfilled into soft gelatin capsules.

EXAMPLE 6

Capmur MCM C₈ (9.0000 kg) was added to a 40 L pot and melted to ahomogenous liquid at 40° C. to 50° C. The Capmul® MCM C₈ was stirredthoroughly with a pneumatic air stirrer at a setting of #20, withnitrogen purge. Cremophor® EL (13.4865 kg), LABRASOL® (1.5750 kg),LABRAFAC LIPOPHILE WL 1349 (0.6750 kg) and vitamin E (0.0135 kg) wereadded to the pot and the contents of the pot were mixed for 15 minutes.The liquid was then cooled to ambient temperature (20° C.-30° C.)without stirring. The stirrer was restarted at a slow speed and thecyclosporin (2.2500 kg) was slowly added to the pot. The stirrer speedwas, gradually increased so that the cyclosporin powder was folded intothe liquid at the minimal vortex formed by the mixer action. Mixing wascontinued until the cyclosporin powder was completely dissolved and theliquid appeared clear. Microscopic analysis revealed no crystals. Thesolution was vacuum deaerated no more than 4 hours prior toencapsulation. The composition was used to fill 90,000 soft gelatincapsules each containing 25 mg of cyclosporin.

EXAMPLE 7

A batch of 22,500 soft gelatin capsules each containing 100 mg ofcyclosporin was prepared according to the procedure described in Example6, utilizing the following quantities:

Quantity Ingredients Added (kg) mg/unit Cyclosporin-A USP 2.2500 100.00Capmul ® MCM C₈ 9.0000 400.00 Cremophor ® EL 13.4865 599.40 LABRASOL ®1.5750 70.00 LABRAFAC LIPOPHILE WL 0.6750 30.00 Vitamin E 0.0135 0.60

The solution appeared clear by visual examination, and a microscopicanalysis revealed no crystals. An amount of the solution, such that eachcapsule contained 100 mg of cyclosporin, was used to fill 22,500 softgelatin capsules.

EXAMPLE 8

Capmul® MCM C₈ (416.67 mg) was melted to a homogenous liquid at about40° C. to 50° C. Cremophor® EL (500 mg) and vitamin E (0.25 mg) wereadded to the melted Capmul® MCM C₈ and the mixture was stirred for 15minutes. Cyclosporin (83.33 mg) was added and mixing continued until thecyclosporin was completely dissolved. The solution, which appeared clearby visual examination, was used to fill soft gelatin capsules. Nocrystals were revealed by a microscopic analysis.

EXAMPLE 9

A batch of 10 soft gelatin capsules, each containing 100 mg ofcyclosporin, was prepared according to the procedure described inExample 8. Because of the smaller scale of the batch, the ingredientswere mixed with a magnetic stirrer in a beaker. The followingingredients, in the listed amounts, were utilized:

Ingredients Quantity (g) mg/unit Cyclosporin-A USP 1.00 100.00 CAPMUL ®MCM C₈ 3.00 300.00 CREMOPHOR ® RH40 8.00 800.00 Total 12.00 1200.00

The resulting solution was clear by visual examination.

EXAMPLE 10

A batch of 10 soft gelatin capsules, each containing 100 mg ofcyclosporin, was prepared according to the procedure described inExample 8. Because of the smaller scale of the batch, the ingredientswere mixed with a magnetic stirrer in a beaker. The followingingredients, in the listed amounts, were utilized:

Ingredients Quantity (g) mg/unit Cyclosporin-A USP 1.00 100.00 CAPMUL ®MCM C₈ 1.00 100.00 CREMOPHOR ® RH40 6.00 600.00 LABRAFAC ® CM10* 4.00400.00 Total 12.00 1200.00 *LABRAFAC ® CM10* is a commercially availablemixture of 70 wt. % LABRASOL ® and 30 wt. % LABRAFAC ® LIPOPHILE, soldby Gattefosse Corporation of Lyon, France.

The resulting solution was clear by visual examination.

COMPARATIVE EXAMPLES 1-5

Five cyclosporin formulations were prepared without a polar lipidcomponent according to the following table. All quantities are listed ingrams.

Compar- Compar- Compar- Compar- Compar- ative Ex- ative Ex- ative Ex-ative Ex- ative Ex- Ingredients ample 1 ample 2 ample 3 ample 4 ample 5Cyclosporin 1.00 0.50 1.00 1.00 0.50 LABRA- 5.04 2.50 2.50 9.01 2.52SOL ® PEG-400 2.55 1.52 5.51 1.10 — Corn Oil — — — — 2.51 Total 8.594.52 9.01 11.11  5.53

Each of the compositions of Comparative Examples 1-5, was a hazy liquid.Microscopic analysis revealed the presence of undissolved crystals inall five of the mixtures.

Compositions of the present invention may be used as liquids for oraladministration or encapsulated, for example, in soft or hard gelatinshells or capsules. The following is a gel formulation that can beemployed

Ingredients Amounts (kg) Gelatin NF 45.500 Glycerin USP 7.830 PurifiedWater 28.500 Sorbitol Special 76% 14.500 Titanium Mass 5.506

Finally, although the invention has been described with reference toparticular means, materials, and embodiments, it should be noted thatthe invention is not limited to the particulars disclosed, and extendsto all equivalents within the scope of the claims.

1-19. (canceled)
 20. A composition for oral administration comprising: acyclosporin and a carrier medium; wherein the carrier medium is selectedto cause the composition, on contact with an aqueous phase, tospontaneously form a clear, fine emulsion of mean particle size of lessthan about 50 nm, wherein the composition does not contain a hydrophilicphase, and wherein the composition comprises a polyoxyethylated naturalvegetable oil, a polyoxyethylated hydrogenated vegetable oil, or amixture thereof.
 21. The composition of claim 20, wherein thecomposition comprises PEG castor oil.
 22. The composition of claim 20,further comprising a monoglyceride, a diglyceride, a medium-chaintriglyceride, or a combination thereof.
 23. The composition of claim 20,further comprising a monoglyceride, a diglyceride, or a combinationthereof.
 24. The composition of claim 20, wherein the compositioncomprises polysorbate
 80. 25. The composition of claim 20, wherein thecomposition comprises polysorbate
 20. 26. The composition of claim 20,wherein the composition comprises polyglycolyzed glycerides.
 27. Acomposition for oral administration comprising: a cyclosporin and acarrier medium comprising a combination of two or more surfactants;wherein the combination of surfactants are selected to cause thecomposition, on contact with an aqueous phase, to spontaneously form aclear, fine emulsion, and wherein the composition does not contain ahydrophilic phase, and wherein the composition comprises apolyoxyethylated natural vegetable oil, a polyoxyethylated hydrogenatedvegetable oil, or a mixture thereof.